Project description:Immune cell infiltrations with lobular inflammation in the background of steatosis and deregulated gut-liver axis are the cardinal features of non-alcoholic steatohepatitis (NASH). An array of gut microbiota-derived metabolites including short-chain fatty acids (SCFA) multifariously modulates NASH pathogenesis. However, the molecular basis for the favorable impact of sodium butyrate (NaBu), a gut microbiota-derived SCFA, on the immunometabolic homeostasis in NASH remains elusive. We show that NaBu imparts a robust anti-inflammatory effect in lipopolysaccharide (LPS) stimulated or classically activated M1 polarized macrophages and in the diet-induced murine NASH model. Moreover, it impedes monocyte-derived inflammatory macrophage recruitment in liver parenchyma and induces apoptosis of proinflammatory liver macrophages (LM) in NASH livers. Mechanistically, by histone deactylase (HDAC) inhibition NaBu enhanced acetylation of canonical NF-κB subunit p65 along with its differential recruitment to the proinflammatory gene promoters independent of its nuclear translocation. NaBu-treated macrophages thus exhibit transcriptomic signatures that corroborate with a M2-like prohealing phenotype. NaBu quelled LPS-mediated catabolism and phagocytosis of macrophages, exhibited a differential secretome which consequently resulted in skewing toward prohealing phenotype and induced death of proinflammatory macrophages to abrogate metaflammation in vitro and in vivo. Thus NaBu could be a potential therapeutic as well as preventive agent in mitigating NASH.
Project description:Lipid accumulation associated with immune cell infiltration leading to hepatocellular ballooning and lobular inflammation are the cardinal features of NASH. With onset and development of multi-omics approaches in the last decade, we have been able to comprehend the existence and functionality of gut microbial ecology. Apart from the compositional variation (dysbiosis), functional alteration of the microbial population i.e., the impact of the crosstalk between gut microbiota-derived metabolites with host cells also remains elusive in terms of regulation of immunometabolic homeostasis and overall human health and disease. Sodium butyrate (NaBu), a short chain fatty acid derived metabolite is known to modulate the inflammatory status of NASH pathogenesis; however, its mechanism of action is not clearly deciphered. To unveil the immunomodulatory activity of NaBu, we found robust anti-inflammatory effect of NaBu in diet induced NASH model with reduced macrophage infiltration. Mechanistically, independent of p65 nuclear translocation, by maintaining the enhanced acetylation status of p65 along with differential p65 recruitment to the proinflammatory gene promoter, NaBu suppressed the inflammatory milieu and resulted in better prognosis. Along with transcriptional rewiring, NaBu also altered the metabolic status, modified the functional outcome and exhibited differential secretome which ultimately resulted skewing of macrophages towards a prohealing phenotype and induced autocrine as well as paracrine death of proinflammatory macrophages to abrogate inflammation in both isolated LMs and in vivo model.
